MicroRNA as Epigenetic Modifiers in Endometrial Cancer: A Systematic Review

The objective of this systematic review is to summarize our current knowledge on the influence of miRNAs in the epigenetic deregulation of tumor-related genes in endometrial cancer (EC). We conducted a literature search on the role of miRNAs in the epigenetic regulation of EC applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following terms were used: microRNA, miRNA, miR, endometrial cancer, endometrium, epigenetic, epimutation, hypermethylation, lynch, deacetylase, DICER, novel biomarker, histone, chromatin. The miRNAs were classified and are presented according to their function (tumor suppressor or onco-miRNA), their targets (when known), their expression levels in EC tissue vs the normal surrounding tissue, and the degree of DNA methylation in miRNA loci and CpG sites. Data were collected from 201 articles, including 190 original articles, published between November 1, 2008 and September 30, 2020 identifying 313 different miRNAs implicated in epigenetic regulation of EC. Overall, we identified a total of 148 miRNAs with decreased expression in EC, 140 miRNAs with increased expression in EC, and 22 miRNAs with discordant expression levels. The literature implicated different epigenetic phenomena including altered miRNA expression levels (miR-182, -230), changes in the methylation of miRNA loci (miR-34b, -129-2, -130a/b, -152, -200b, -625) and increased/decreased methylation of target genes (miR-30d,-191). This work provides an overview of all miRNAs reported to be involved in epigenetic regulation in EC including DNA methylation and RNA-associated silencing. These findings may contribute to novel strategies in diagnosis, risk assessment, and treatments aimed at miRNAs, their target genes or DNA methylation.